Fast and efficient synthesis of 4-arylidene-3-phenylisoxazol-5-ones

Article abstract of DOI:10.1155/2012/562138

A convenient and easy synthesis of 4-arylidene-3-phenylisoxazol-5-ones by the three-component reaction of hydroxylamine, ethyl benzoylacetate and aromatic aldehydes in the presence of DABCO in refluxing ethanol is reported.

Full text of DOI:10.1155/2012/562138

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2012, 9(1), 425-429
http://www.e-journals.net
Fast and Efficient Synthesis of
4-Arylidene-3-phenylisoxazol-5-ones
MARYAM MIRZAZADEH* and GHOLAM HOSSEIN MAHDAVINIA
*Department of Chemistry, Firoozabad Branch
Islamic Azad University, Fars, Iran
Department of Chemistry, Marvdasht Branch
Islamic Azad University, Fars, Iran
mirzazadeh_maryam@yahoo.com
Received 2 July 2011; Accepted 27 August 2011
Abstract: A convenient and easy synthesis of 4-arylidene-3-phenylisoxazol-5-ones
by the three-component reaction of hydroxylamine, ethyl benzoylacetate and
aromatic aldehydes in the presence of DABCO in refluxing ethanol is reported.
Keywords: One-pot, Isoxazole, DABCO, MCRs
Introduction
Isoxazoles and its derivatives represent useful synthetic building blocks1. They are an
important class of heterocycles compounds, which are employed in the area of
pharmaceuticals and therapeutic such as antimicrobial, antifungal2, anticancer3, ulcerogenic4
and anti-inflammatory5. Therefore, various synthetic methods have been reported to access
the isoxazole derivatives6.
Multicomponent coupling reactions (MCRs) involving domino processes, in which
several reactions are combined into one synthetic operation have emerged as a powerful
valuable synthetic tool in organic synthesis7. MCRs have some advantages over classical
multistep syntheses, including cost-effective, requiring a minimum of time, simple
procedures, high degrees of atom economy, the possibility for combinatorial surveying of
structural variations and environmental friendliness8. The preparation of heterocyclic
systems using MCRs often involves classical carbonyl condensation chemistry. Among
various carbonyl structures, 1,3-dicarbonyl compounds constitute important synthetic
building blocks and intermediates, incorporating multiple functionalities that can be
involved either as nucleophilic or electrophilic species in a variety of synthetic
transformations9. Thus, the high synthetic potential of these easily accessible reagents has
found numerous applications, especially for the synthesis of heterocyclic structures10.

426
MARYAM MIRZAZADEH et al.
The conventional synthesis of 4-arylidene-3-phenylisoxazol-5-one to be fulfilled in two
steps, in the first step, preparation of oxime [ethyl 3-(hydroxyimino)-3-phenylpropanoate]
and ring closing of this oxime to afford 3-phenylisoxazol-5-one. Then in second step, the
Knoevenagel condensation of aryl aldehydes and 3-phenylisoxazol-5-one produce
4-arylidene-3-phenylisoxazol-5-ones11,12
.
Recently one-pot synthesis of these compounds catalyzed by pyridine is reported13.
However, the use of toxic reagent (pyridine), long reaction time, low yields are among the
drawbacks of this reported method. We herein described a facile synthesis of 4-arylidene-3-
phenylisoxazol-5-one derivatives by three-component condensation of ethyl benzoylacetate,
hydroxylamine and aldehyde, in ethanol using DABCO, as weak and safe base, at reflux
condition (Scheme 1).
Ar
Ph
H
O
O
O
DABCO
NH2OH.HCl
+
+
N
Ar
H
O
Ph
OEt
EtOH, Reflux
O
1
2
4
3
Scheme 1. DABCO-promoted synthesis of 4-arylidene-3-phenylisoxazol-5-ones
Experimental
A mixture of 2 mmol ethyl benzoylacetate (1), 2 mmol hydroxylamine hydrochloride (2)
and 1.1 mmol DABCO in 4 mL ethanol was refluxed for 3 min, after then 2 mmol aromatic
aldehyde (3) was added and the mixture was further refluxed for 1-15 min. After completion
of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature
and the resulting crystal product (4) was collected by filtration and washed with water. The
product was found to be pure and no further purification was necessary.
Results and Discussion
In our initial experiments toward the development of this reaction, we have reacted
4-methoxybenzaldehyde (1.0 mmol) with hydroxylamine hydrochloride (1.0 mmol) and
ethyl benzoylacetate (1.0 mmol) in ethanol, but no resulting product has been found at room
temperature and reflux conditions. It was observed that the same reaction proceeded when
we use DABCO in ethanol at room temperature yielding the corresponding 4-arylidene-3-
phenylisoxazol-5-one in 43% yield after 30 min. When we attempted the same reaction in
ethanol at reflux condition, the reaction proceeded to completion within 4 min and yielded
the corresponding 4-arylidene-3-phenylisoxazol-5-one in 90% yield. Encouraged by this
result we have explored the efficiency of various bases on the reaction. Among the bases
tested for this condensation reaction to yield 4-(4-methoxybenzylidene)-3-phenylisoxazol-5-
one, are triethyl amine (65%), pyridine (77%)13, piperidine (75%), DBU (78%) and DABCO
(82%). However DABCO gave excellent yields.
In order to determine the most appropriate choice of solvent system for this DABCO-
promoted synthesis of 4-arylidene-3-phenylisoxazol-5-ones, we have screened the solvents
such as methanol (70%), ethanol (82%) and water (52%). Of the solvents tested in the
screening we got the maximum yield of the product in shorter reaction times, when we use
ethanol as solvent.
In order to determine the scope of this reaction, we have synthesized differently
substituted 4-arylidene-3-phenylisoxazol-5-ones by varying differently substituted
aldehydes including both electron-donating and electron-withdrawing groups. It is observed

Fast and Efficient Synthesis of 4-Arylidene-3-Phenylisoxazol-5-ones
427
that the reaction gave good yields of products with faster reaction rate when the aldehydes
bearing electron-donating group is used compared to the aldehydes with electron-
withdrawing groups. The corresponding results are tabulated in Table 1.
Table 1. Preparation of 4-arylidene-3-phenylisoxazol-5-ones
Entry
1
Ar
C6H5
4-Cl
Product Time, min
12
15
Yield, %
70
65
Mp, ºC
210-212
171-173
175-177
187-188
165-167
210
Lit. Mp, ºC
215-216[13]
4a
4b
2
175-176[13]
---
3
4-Br
4-CH3
15
10
4
60
80
4c
4d
4e
4f
4
189-191[13]
5
6
4-OCH3
4-OH
82
75
168-169[13]
---
4
7
4-Me2N-C6H4
2-OCH3
2-Naphthyl
2,4-OCH3
2,4-OH
PhCH=CH2
4
85
78
195-196
162-164
184-186
210-213
259(dec.)
156
194-196[13]
4g
4h
4i
8
6
---
---
---
---
---
9
10
1
70
85
10
11
12
4j
1.5
15
80
65
4k
4l
The plausible mechanism for the synthesis of 4-arylidene-3-phenylisoxazol-5-ones in
the presence of DABCO involves the initial reaction of DABCO with hydroxylamine
hydrochloride for repudiation of hydroxylamine which attacked to ethyl benzoylacetate to
the formation of oxime then ring closing of oxime gives 3-phenylisoxazol-5-one. Reaction
of DABCO with aldehyde leading to the formation of intermediate (A), which attacked by
the 3-phenylisoxazol-5-one gives another intermediate (B) with subsequent elimination of
H2O leads to the desired product (Scheme 2). All the unknown products were characterized
by 1H, 13C NMR and IR
N
Ph
N
Ph
OH2
[B]
O
O
OEt
O
H
N
EtOH
HO
O
O
O
OEt
Ph
O
O
Ph
O
N
Ph
NH2OH
N
[A]
OH
N
N
NH2OH.HCl
N
N
NH
Cl
N
H
O
N
Scheme 2. Plausible mechanistic pathway for the formation of 4-arylidene-3-
phenylisoxazol-5-ones

428
MARYAM MIRZAZADEH et al.
Spectral Data
4-(4-Bromobenzylidene)-3-phenylisoxazol-5-one (4c)
1
IR (KBr): 3100, 1745, 1613, 1545, 1488,1072 cm−1; H NMR (400 MHz, CDCl3): δ 7.46
(s, 1H, ArCH=), 7.61-7.53 (m, 5H, Ph-H), 7.64 (d, 2H, J = 8.4 Hz, ArH), 8.19 (d, 2H,
J = 8.4 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 119.39, 127.15, 128.18, 128.74, 128.95,
129.39, 129.64, 130.87, 131.14, 131.65, 132.43, 133.38, 135.19, 151.09, 163.92, 168.00.
4-(4-Hydroxybenzylidene)-3-phenylisoxazol-5(4H)-one (4f)
IR (KBr): 3357, 3050, 1725, 1580, 1531, 1448, 1375, 1301, 1225 cm−1; 1H NMR (400 MHz,
DMSO-d6): δ 6.92 (d, 2H, J = 8.8, ArH), 7.56-7.65 (m, 6H, Ph-H, ArCH=), 8.41 (d, 2H,
J = 8.8, ArH), 11.12 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): δ 113.22, 116.62,
124.89, 127.94, 129.30, 129.69, 131.27, 136.88, 138.52, 153.74, 164.76, 169.39.
4-(2-Methoxybenzylidene)-3-phenylisoxazol-5-one (4h)
1
IR (KBr): 3065, 1739, 1587, 1543, 1476, 1365, 1251, 1169 cm−1; H NMR (400 MHz,
CDCl3): δ 3.84 (s, 3H, OMe), 6.93 (d, 1H, J = 8.4 Hz, ArH ), 7.08 (t, 1H, J = 7.6 Hz, ArH),
7.24-7.28 (m, 1H, ArH), 7.53-7.6 (m, 5H, Ph-H), 8.25 (s, 1H, ArCH=), 8.85 (d, 1H, J = 8.0
Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 55.93, 117.14, 119.70, 121.82, 127.72, 127.90,
128.55, 128.76, 129.19, 130.37, 130.93, 133.45, 136.56, 147.33, 160.05, 164.21, 168.58.
4-(Naphthalen-2-ylmethylene)-3-phenylisoxazol-5(4H)-one (4i)
1
IR (KBr): 3050, 1743, 1592, 1542, 1377, 1269, 1069 cm−1; H NMR (400 MHz, CDCl3):
δ 7.54-7.94 (m, 11H, Ph-H, ArH), 8.46 (dd, 1H, J = 8.6 Hz, J = 1.2 Hz, ArH), 8.80 (s, 1H,
ArCH=); 13C NMR (100 MHz, CDCl3): δ 118.54, 127.13, 127.50, 127.86, 128.28, 128.59,
128.74, 128.84, 128.88, 129.36, 129.72, 129.98, 130.21, 131.05, 132.75, 135.82, 137.11,
152.75, 164.19, 168.32.
4-(2,4-Dimethoxybenzylidene)-3-phenylisoxazol-5(4H)-one (4j)
IR (KBr): 3072, 1741, 1572, 1534, 1504, 1473, 1428, 1379, 1272, 1213,1083 cm−1; 1H NMR
(400 MHz, CDCl3): δ 3.80(s, 3H, OMe), 3.91 (s, 3H, OMe), 6.39 (d, 1H, J = 2.0 Hz, ArH),
6.64 (dd, 1H, J = 9.1 Hz, J = 2.0 Hz, ArH), 7.53-7.63 (m, 5H, Ph-H), 8.18 (s, 1H, ArCH=),
9.21 (d, 1H, J = 9.1 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 55.88, 55.99, 97.75, 105.99,
113.53, 115.67, 127.98, 128.20, 128.72, 128.85, 129.06, 130.63, 136.36, 146.15, 162.59,
164.68, 167.30, 169.64.
4-(2,4-Dihydroxybenzylidene)-3-phenylisoxazol-5(4H)-one(4k)
IR (KBr): 3339, 3095, 1726, 1625, 1581, 1537, 1476, 1391, 1317, 1242, 1190, 1092 cm−1;
1H NMR (400 MHz, DMSO-d6): δ 6.37 (d, 1H, J= 1.6 Hz, ArH), 6.37 (dd, 1H, J = 9.0 Hz,
J = 1.6 Hz, ArH), 7.59 (s, 5H, Ph-H), 8.05 (s, 1H, ArCH=), 9.04 (d, 1H, J = 9.0 Hz, ArH),
11.09 (s, 2H, OH); 13C NMR (100 MHz, DMSO-d6): δ 102.10, 109.80, 113.82, 128.46,
129.27, 129.62, 131.16, 136.01, 146.59, 164.06, 165.33, 167.74, 170.09.
3-Phenyl-4-(-3-phenylallylidene) isoxazol-5(4H)-one (4l)
IR (KBr): 3080, 1747, 1610, 1535,1493, 1445, 1392, 1175, 1098 cm−1; 1H NMR (400 MHz,
CDCl3): δ 7.30 (d, 1H, , J= 15.6 Hz, =CH) 7.40-7.46 (m, 3H, ArH, Ph-H), 7.50 (d, 1H, J= 12
Hz, ArCH=), 7.55-7.66 (m, 7H, ArH, Ph-H), 8.43 (dd, 1H, J= 15.6 Hz, J= 12 Hz, CH=); 13C
NMR (100 MHz, CDCl3): δ 116.53, 122.78, 127.53, 128.22, 128.60, 129.09, 129.24, 129.29,
131.01, 131.63, 131.71, 135.00, 148.40, 150.08, 151.41, 152.33, 162.29, 169.31.

Fast and Efficient Synthesis of 4-Arylidene-3-Phenylisoxazol-5-ones
429
Conclusion
In conclusion, we have developed a clean, efficient, convenient, simple and fast method for
the synthesis of 4-arylidene-3-phenylisoxazol-5-ones in good yield via one-pot synthetic
route. Present methodology offers very attractive features such as reduced reaction times,
higher yields, easy work-up and economic viability of the promoter, when compared with
conventional methods as well as with other catalysts.
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